Leveraging Glycoscience to Tackle Infectious Diseases

Even as more advanced tools and technologies become available for studying transmission, infectivity, and resistance to infectious diseases, glycobiology’s promise remains underappreciated. Glycobiology encompasses the structure and function of glycans—the complex, branched chains of polysaccharides and oligosaccharides that link to proteins and lipids in nearly all cells and tissues.

To make real progress in infectious disease research, we need a better understanding of how the unique glycans present on the cell surfaces, bacteria, and viruses mediate their interactions and the host immune response.

Glycosylation is ubiquitous

Glycosylation is a fundamental lever that regulates countless biological processes via posttranslational modification. Infection and immunity are no exception. Just as each human cell is covered with a unique assortment of glycans, bacteria, and viruses bear their own glycan combinations that mediate their interactions with host cells.

For example, approximately half of all mammalian virus families use host glycans attached to glycolipids or glycoproteins as receptors for binding and infecting cells. In bacteria, lectins—proteins that bind specific glycans—often mediate adhesion to host cell glycoproteins and other structures. Bacterial surface glycans can also cloak target protein structures to evade antibody recognition.

Understanding how glycosylation contributes to bacterial and viral susceptibility, immunity, and infection severity can help us develop more effective approaches to preventing and fighting infectious diseases.

Glycan recognition is a fundamental part of the immune system’s determination of “self” versus “other.” Innate immune cell pattern recognition receptors (PRRs) recognize pathogen-associated glycans and initiate signaling cascades that modulate immune responses. These host–pathogen interactions could be leveraged to develop more effective vaccines and therapeutics. For example, researchers have explored viral prophylactics that interfere with virus–host cell receptor interactions by masking cell surface glycans with engineered proteins. Additionally, recent research has demonstrated the role of glycosylation in maintaining healthy gut microbiota that can prevent Clostridioides difficile infection.

Though we are still far from realizing glycobiology’s full potential in infectious disease research, several recent developments in the field highlight the progress made thus far and signal future directions.

Lessons learned from SARS-CoV-2

The COVID-19 pandemic drove a wealth of research dedicated to understanding viral transmission, infectivity, and susceptibility, some of which elucidated glycobiology’s involvement in these processes. The role of glycosylation in modulating immunoglobulin G (IgG) effector functions was already well established, but further research demonstrated that differences in IgG glycosylation profiles were associated with COVID-19 disease course and severity. Additionally, overall levels of α2,6-sialylation, one type of glycan linkage, were increased in the plasma and lung tissue of patients with severe COVID-19. These findings illustrate how glycans could be important biomarkers of infectious disease severity.

Glycobiology research also provided insight into viral infectivity and potential antiviral strategies. Glycosylation of the SARS-CoV-2 spike (S) protein is an important component of the receptor binding domain’s conformational plasticity, allowing the virus to successfully bind to the host ACE2 receptor. S protein glycans also help mask viral surface proteins, limiting neutralizing antibody access and promoting successful infection.

Increased understanding of the role of S protein glycosylation in SARS-CoV-2 infection also informed experimental antivirals, such as an engineered banana lectin that binds to S protein glycans to prevent successful association with cellular ACE2 receptors.

Leveraging glycans as a vaccine target

Recent research has also used our understanding of glycans to develop more successful vaccines. Glycoconjugate vaccines developed from bacterial capsule polysaccharides have been used for nearly 40 years to prevent bacterial infections. Recent work has focused on the development of synthetic carbohydrate antigens to replace the need for glycan antigens obtained through bacterial fermentation, with successful candidate vaccines developed for meningococcal meningitis, pneumococcal pneumonia, and more. Another promising approach to creating more broadly efficacious vaccines involves leveraging cross-reactive synthetic saccharide fragments containing structures shared by different bacterial serotypes.

But the role of glycoscience in vaccine development is not limited to bacterial pathogens. As nucleic acid vaccines come under wider study for viral infections, research has illustrated how host glycosylation of protein antigens translated from these vaccines can impact their efficacy and are, therefore, an important consideration in their design.

Fighting antimicrobial resistance with glycobiology

Antimicrobial resistance is an urgent public health concern, largely driven by the misuse and overuse of antimicrobials. A dearth of novel and innovative antimicrobial strategies has held back progress in fighting drug-resistant pathogens.

Glycosylation represents a strong potential pathway in developing new antibacterial strategies because of its role in the virulence of many bacterial pathogens. By targeting the unique glycosylation systems of these pathogens, new antivirulence therapies could work to alleviate pathogenicity rather than eliminating a bacterial population altogether, forestalling the development of drug-resistant bacteria.

The creation of synthetic carbohydrates to advance glycoconjugate vaccines may also be an important step in preventing the spread of pathogens that are recognized as AMR threats, but cannot currently be prevented by vaccination.

Recent research has highlighted the massive potential of glycobiology research in improving our understanding of infectious diseases. Further advances in tools such as glycan microarrays and other technologies to better understand host–pathogen glycan interactions will unlock new and expanded applications in infectious disease prevention and therapeutics.